PROJECT SUMMARY Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and has one of the worst 1- year survival rates of any cancer. There is a major need for understanding of the molecular mechanisms leading to HCC and developing novel strategies for effective prevention and treatment. HCC arises exclusively on the background of chronic liver injury and inflammation. Thus, targeting key genes that regulate both inflammation and oncogenic pathways in HCC appears to be an attractive therapeutic approach. RNA-binding protein Hu Antigen R (HuR) is one such candidate that controls the translation of multiple genes involved in inflammation and oncogenic signaling pathways through binding to the adenine- and uridine-rich elements located on 3'-untranslated region (UTR). Abnormal increase and cytoplasmic distribution of HuR has been linked to carcinogenesis in many types of cancers. However, little is known about the regulation and in vivo function of HuR in liver pathophysiology and carcinogenesis, largely due to the embryonic lethality of whole body HuR-null mice. Our previous studies have demonstrated that small heterodimer partner (Shp, Nr0b2), a nuclear receptor highly expressed in normal hepatocytes, is a tumor suppressor in HCC. We recently identified that HuR is activated in Shp-deficient hepatocytes and is transported to macrophages via exosomes, stimulating macrophage pro-inflammatory activation. The objective of this application is to characterize the role and molecular mechanism by which HuR regulates liver inflammation and hepatocarcinogenesis, and further test interventions to specifically target HuR for HCC prevention and treatment. Our central hypothesis is that the activation of HuR in hepatocytes promotes multiple oncogenic pathway activation as well as the exosome- stimulated liver inflammation that enhances liver carcinogenesis, while HuR inhibitor suppresses both liver inflammation and oncogenic pathways activation, leading to inhibition on HCC. In order to accomplish our goals, we propose the following specific aims: Aim 1. Characterize the molecular mechanisms that lead to HuR activation during hepatocarcinogenesis. Aim 2. Determine the function impact and downstream signaling of HuR in driving liver inflammation and carcinogenesis using hepatocyte-specific gene knockout mouse model. Aim 3. Evaluate the anti-tumor efficiency of a novel HuR inhibitor in HCC models. Our study will provide a foundation for understanding the role of HuR in liver pathophysiology and carcinogenesis. If the proposed aims are accomplished, the possibility of targeting HuR for HCC prevention and treatment will emerge, making this project of high clinical significance and translational value.